key: cord-0857772-1jtzcesy
authors: Lanaspa, Miguel; Annamalay, Alicia A; LeSouëf, Peter; Bassat, Quique
title: Epidemiology, etiology, x-ray features, importance of co-infections and clinical features of viral pneumonia in developing countries
date: 2014-01-10
journal: Expert Rev Anti Infect Ther
DOI: 10.1586/14787210.2014.866517
sha: 1591aeacef943983aa084bd28a8da7b544d69684
doc_id: 857772
cord_uid: 1jtzcesy

Pneumonia is still the number one killer of young children globally, accounting for 18% of mortality in children under 5 years of age. An estimated 120 million new cases of pneumonia occur globally each year. In developing countries, management and prevention efforts against pneumonia have traditionally focused on bacterial pathogens. More recently however, viral pathogens have gained attention as a result of improved diagnostic methods, such as polymerase chain reaction, outbreaks of severe disease caused by emerging pathogens, discovery of new respiratory viruses as well as the decrease in bacterial pneumonia as a consequence of the introduction of highly effective conjugate vaccines. Although the epidemiology, etiology and clinical characterization of viral infections are being studied extensively in the developed world, little data are available from low- and middle-income countries. In this paper, we review the epidemiology, etiology, clinical and radiological features of viral pneumonia in developing countries.

Pneumonia is still the number one killer of young children globally, accounting for 18% of mortality in children under 5 years of age. An estimated 120 million new cases of pneumonia occur globally each year. In developing countries, management and prevention efforts against pneumonia have traditionally focused on bacterial pathogens. More recently however, viral pathogens have gained attention as a result of improved diagnostic methods, such as polymerase chain reaction, outbreaks of severe disease caused by emerging pathogens, discovery of new respiratory viruses as well as the decrease in bacterial pneumonia as a consequence of the introduction of highly effective conjugate vaccines. Although the epidemiology, etiology and clinical characterization of viral infections are being studied extensively in the developed world, little data are available from low-and middle-income countries. In this paper, we review the epidemiology, etiology, clinical and radiological features of viral pneumonia in developing countries.

Despite significant reductions in child mortality over the last decade, pneumonia remains the leading cause of childhood mortality worldwide, accounting for 18% of deaths in children under 5 years of age [1] . An estimated 120 million new cases of pneumonia occur globally each year [2] . In addition, an estimated 14.9 million (95% CI: 12.4-18.1 million) episodes of severe and very severe acute lower respiratory infections (ALRI) in young children result in hospital admissions [3] . In developing countries, management and prevention efforts against pneumonia have traditionally focused on bacterial pathogens, known to cause between 30 and 77% of the most severe pneumonia cases [4] [5] [6] . Among these pathogens, two bacteria stand out as the major causes of disease: Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) [5] [6] [7] [8] [9] . The scarcity of routine microbiology facilities in most resource-constrained settings and the low sensitivity of current bacterial identification methods hinder adequate surveillance, which may in turn contribute to an underestimation of the real burden of these pathogens. The relevance and impact of bacteria as a cause of pneumonia was clearly established prior to the introduction of the pneumococcal and Hib conjugate vaccines [8] [9] [10] [11] . More recently, however, attention has shifted toward non-bacterial causes of pneumonia, namely, to viral respiratory infections. Respiratory syncytial virus (RSV), widely studied in both developed and developing countries, is estimated to cause over 22% of all ALRI and up to 200,000 deaths annually [12] . In addition to RSV, other viruses have emerged as major causes of pneumonia and other potentially life-threatening respiratory syndromes. Viral pathogens have gained recent interest as a result of improved diagnostic methods such as PCR, outbreaks of severe disease caused by emerging pathogens such as avian influenza A (H5N1) and pandemic influenza A (H1N1) and the discovery of new respiratory viruses such as human metapneumovirus (hMPV), human coronavirus (hCoV), human bocavirus (hBoV) and human rhinovirus (HRV) species C. Furthermore, the introduction of highly effective conjugate vaccines globally has led to a decrease in bacterial pneumonia, and consequently, a rise in the prominence of viruses. Although the epidemiology, etiology and clinical characterization of such infections in children are currently being studied extensively in the developed world, very little microbiologically confirmed data are available from low-and even middleincome countries [13] . In this paper, we review the epidemiology, etiology, clinical and radiological features of viral pneumonia in developing countries. Data have been retrieved from countries highlighted in FIGURE 1.

A major challenge of reviewing published literature on acute respiratory infections (ARI) in children is the lack of a gold standard, universally accepted case definition for pneumonia [14] . The lack of a gold standard definition has hampered a homogenous approach to pneumonia research for decades. Therefore, we decided to use a non-restrictive approach during this systematic literature search to incorporate the wide variety of utilized case definitions for pneumonia (TABLE 1) .

We defined 'developing country' using the World Bank and International Monetary Found (IMF) classifications and included studies performed in countries in the newly industrialized category as of 2011, including Brazil, People's Republic of China, India, Mexico, Philippines, South Africa, Thailand and Turkey (IMF 2011).

We undertook a systematic literature review using various search terms in Medline and Embase (APPENDIX 1) as well as hand-searched online journals so as to include the different age ranges, inclusion criteria (ARI, ALRI, severe ALRI, very severe ALRI, influenza-like illness, radiologically confirmed pneumonia and WHO-defined pneumonia), the different detection techniques utilized for viral detection (PCR, immunofluorescent antibody test, enzyme-linked immunosorbent assay, shell-vial and viral culture); the different number of virus studied (from single virus detection studies to multiple-viral detection studies) and finally the different samples studied (nasopharyngeal aspirates [NPA], nasal and pharyngeal swabs, bronchial aspirates and lung punctures).

To address public health issues, a thorough knowledge of the epidemiology of viral pneumonia is mandatory. While the epidemiology of ARI in the developed world has been adequately characterized, this is not the case for most developing countries where there is a scarcity of reliable surveillance data. In resource-constrained settings, incidence calculations are either roughly estimated or based on a limited number of geographically limited areas under demographic surveillance systems (DSS) set up in the context of research efforts. Furthermore in such settings, data from adults and elderly patients are Review Lanaspa, Annamalay, LeSouëf & Bassat extremely scarce, if not, unexistent. In developed countries, the incidence of ARI is highest among children younger than 5 years of age, decreasing greatly after 15 years of age and increasing again among adults older than 75 years of age [13] . The few available data from the developing world suggests similar age-distribution tendencies, although a rise in pneumonia incidence has been observed among young adults in settings with high HIV prevalence [15] .

A total of 21 studies from South America [16] [17] [18] , Asia [19] [20] [21] [22] [23] [24] [25] [26] [27] and Africa [25, [28] [29] [30] [31] [32] [33] [34] [35] presented incidence data on ALRI and virus-specific associated ALRI, 4 of which presented incidences in adults [19, 22, 24, 30] . Incidence rates are summarized in In the pediatric populations from African settings, the incidence of ALRI ranged from 90 to 1029 cases per 1000 children-year-at-risk (CYAR) for all ALRI, and from 13.2 to 560 cases per 1000 CYAR for severe ALRI. In Asian settings, the incidence of ALRI and severe ALRI ranged from 21.7 to 730 and from 16 to 210 cases per 1000 CYAR, respectively. In South America, only incidences of all ALRI cases (and not for severe cases) were available, ranging from 64 to 1710 cases per 1000 CYAR. Discrepancies between the different settings may in part be explained by differences in age groups, year of study and definitions hampering accurate epidemiological comparisons among regions. Children under 1 year of age have the Vong et al. (2013) >5 ALRI Symptoms onset £14 days AND fever ‡38˚C or history of fever during the last 3 days AND cough AND one of the following: dyspnea, chest pain or crackles on auscultation [79] Feikin et al. (2012) >5 ALRI Cough or difficulty breathing or chest pain AND fever ‡38˚C or oxygen saturation £90% or hospitalization [28] Only studies including at least 1000 subjects published during the last 5 years have been considered. † WHO case definition: age-specific tachypnea AND cough and/or difficulty in breathing. ALRI: Acute lower respiratory infection; CAP: Community-acquired pneumonia; LRTI: Lower respiratory tract infection.

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Before 2000, few studies recruited for more than 12 consecutive months and hence seasonality could not always be inferred [36] .

Since then, there have been several reports on site-specific virus seasonality, especially for RSV, influenza virus and hMPV (TABLE 6) . RSV and hMPV in particular seem to be more frequently detected during the rainy season in America, Africa and Asia, with the exception of Nigeria and South Africa where RSV showed higher incidence during the dry season [51, 52] . Interestingly, 30% of lung samples from 98 fatal pneumonia episodes in children under the age of 2 from Mexico were positive for RSV [53] . HRV was the second more frequently reported virus, although in some studies it ranked first, especially in children over the age of 2 [52] . In all ALRI and in severe ALRI, HRV was detected in 21-40 and 20-41%, respectively. In studies that further typed HRV, HRV-A was the most frequently identified species in both severe and nonsevere ALRI while HRV-B was rarely detected [47, [54] [55] [56] [57] [58] [59] . HRV species distribution was consistent among African, Asian and American settings, although recent reports from non-developing settings, namely Australia, have highlighted the pathogenic role of the newly described HRV-C and its potential impact as a cause of pediatric severe respiratory disease and hospital admissions [60] . ADV, influenza and PIV were recorded in 4-37, 3-16 and 5-23% of ALRI cases, respectively. However, ADV was consistently more frequently identified than RSV in samples from Mozambique in three large studies [33, 48, 61] , two of which were in severe ALRI cases in children under the age of 5. This trend was not confirmed by other studies with the exception of a Malawian study where 16% of the lung puncture samples in radiologically confirmed pneumonia were 

Review www.expert-reviews.com positive to ADV. In those populations, there is a high burden of HIV and the importance of this condition needs to be further investigated. Of the newly described respiratory viruses, hMPV was recorded in 3-27.2% of ALRI cases, hCoV in 0-9% and hBoV in 0.7-5%. Finally, only two studies reported polyomavirus infection in 3.6 and 25% of ALRI in children under 13 years of age in Philippines, and in children younger than 12 years of age in Thailand, respectively [57, 59] . When considering only the most comprehensive studies (detection by PCR of at least 10 viruses in study populations larger than 500 patients over a minimum 12-month period), the general prevalence of viral infections ranged from 47 to 69%, with HRV, RSV, influenza, ADV and hMPV being the most commonly detected pathogens [29, 33, 42, 44, 45, 48, 59, 62] . Viral etiology can only be inferred if proper case-control studies including healthy and/or asymptomatic children are conducted to compare the prevalence of viral pathogens between both groups and to calculate the attributable fraction. Such a study design, currently being utilized by the Pneumonia Etiology Research for Child Health (PERCH) study [63] , could help clarify the role of some respiratory viruses such as HRV in viral pneumonia. Eleven studies conducted in countries including the Gambia, Kenya, Nepal, Thailand and Vietnam included control groups to compare virus prevalence in patients with either pneumonia, severe pneumonia or radiologically confirmed pneumonia. The only virus indisputably associated with pneumonia was RSV, which was significantly more prevalent in all three pneumonia case definitions and for different age groups. Influenza was related to hospitalized pneumonia in children under the age of 3 [27], but not in children younger than 12 years of age with severe pneumonia. Two studies conducted in Kenya with 810 and 2973 patients with severe pneumonia under the age of 5, respectively, demonstrated variable results with a significant association between influenza and severe pneumonia in the larger study [29, 45] . HRV, hMPV and PIV were mostly unrelated to pneumonia in different casecontrol studies, although a significant association was found between HRV and pneumonia in the 1-4 age group (odds ratio [OR]: 2.3; 95% CI: 1.0-5.2) with the exception of one study of infants from Thailand [22] . In this study, HRV genotypes were typed and significance was only attained for species A and C, but not B. Interestingly, hMPV was only related to pneumonia in children older than 5 years of age, but not in those younger than 5 or in those younger than 12 [28] . Only PIV-3 was associated with an increased risk of pneumonia (OR: 13; 95% CI: 6.0-28.0) in children under the age of 3 [46] . ADV, hCoV and hBoV were not related to pneumonia in any of the case-control studies that included their detection [27] [28] [29] 41, 43, 45 ].

Pneumonia is a major cause of death and hospital admissions in HIV-infected children [64] . In sub-Saharan Africa, where the pediatric HIV epidemic is essentially circumscribed, studies describe singularities in HIV-associated pneumonia. Cytomegalovirus (CMV), a viral pathogen responsible for mononucleosis-like or influenza-like illnesses in immunocompetent children, is a leading cause of pneumonia in HIV-infected children. In a study of children with severe ALRI from South Africa, CMV was identified in 36% of HIV-infected children (and in 15% of uninfected children, most of whom were severely malnourished). Furthermore, CMV was more common than Pneumocystis jirovecii pneumonia (27%) and other viral-associated pneumonia (19%) [65] . In another study, hMPV was indentified as the only infection in 3.7% of HIV-infected and 9.1% of HIV-uninfected children [66] . Other respiratory viruses are also commonly identified among HIV-infected patients with severe ALRI, although less frequently than among HIVuninfected children. One likely explanation for this is the role of other pathogens in severe pneumonia in such immunocompromised patients. In a large study of children younger than 2 years of age admitted for severe pneumonia, viruses and bacteria were identified in 15.7 and 12.5% of HIV-infected patients compared with 34.8 and 5.8% of HIV-uninfected cases, respectively [67] . P. jirovecii was only detected among HIV-infected children. In this study, CMV and hMPV were not tested for, possibly resulting in an underestimation of the relevance of viral pathogens causing ALRI in HIV-infected patients. In such children, polymicrobial infections were more common than in HIV-uninfected patients and also appeared to be associated with a worse prognosis [68] . Clinical features were similar in hMPV-associated ALRI [66] , but not in PIV and influenza-associated ALRI where wheezing was less frequent and alveolar consolidation was more frequent in HIVinfected than in HIV-uninfected children [69, 70] . Fatal outcome was recorded in 0-35% of HIV-infected and in 0-11% of HIV-uninfected children with viral pneumonia, with CMV causing worse prognosis than any other virus (TABLE 8) [65, 67, 69, 70] . Lymphoid interstitial pneumonitis (LIP) is a lymphoproliferative response to HIV and/or Epstein-Barr virus common in HIV-infected children older than 2 years of age without proper antiretroviral treatment [71] [72] [73] . Although LIP is a chronic lung disease, it may present intermittent episodes of ALRI with fever and tachypnea mostly due to bacterial superinfections [74] . Digital cubbling, generalized lymphadenopathy and hepatomegaly are common in children with LIP, and the characteristic radiological findings include persistent, diffuse bilateral reticulonodular pattern [74, 75] .

We identified 13 studies that included adults, 4 of which reported detection rates for both adults and children (TABLE 9 ). Viral detection rates were 20-39% [76] [77] [78] [79] in adult ALRI with the exception of a study in Laos of 34 patients hospitalized with ALRI where 67% of samples were positive to at least one virus [80] . This value must be considered with caution because of the small size of the study. HRV was the most frequently reported virus (6-11.5%) and was detected in all studies where it was tested for. Influenza was detected in 3.1-13% of ALRI adult cases and was usually the second most commonly identified virus after HRV, with the exception of a study conducted in Vietnam during the H1N1 pandemic where influenza was the most frequently detected virus [81] . RSV was documented in 0-13% of cases, hMPV in 0-11.5%, ADV in 0.7-3% and hBoV in 0.7% of adult ALRI cases [43] . Two studies reported data stratified according to age groups for influenza-related ALRI and HRV-related ALRI, showing a decrease of viral detection with age [22, 30] .

Since the advent of multiplex-PCR allowing the simultaneous detection of up to 18 respiratory viruses, multiple viruses in the same specimen have been increasingly identified in pneumonia etiological studies. Multiple viral infections were reported in 5.8-8% of adults and 11-56% of children [80, [82] [83] [84] [85] [86] . Both the lowest and the highest co-infection rates in children were reported from studies using an 18-virus multiplex PCR in similar age groups (<5 years vs <3 years of age), so disparity may be due to epidemiological differences in the various settings. The most frequently detected combination usually included the most prevalent viruses identified in the study (RSV-hMPV, RSV-HRV, RSV-influenza and HRV-ADV). hBoV is frequently detected in association with other respiratory viruses (70-89%), followed by polyomavirus (73%), ADV, hCoV and PIV (60% each) and HRV, hMPV and RSV (50% each) [29, 50, 87] . The clinical relevance of those associations remains unclear and some studies did not find differences in severity due to viral co-detection compared with single virus identification [50, 79, 88] . However, two studies in Mozambique reported multiple viral infections in 11-20% of cases of severe pneumonia and found significant associations with nasal flaring (OR: 2.7; 95% CI: 1.1-6.5), lower chest indrawing (OR: 3.8; 95% CI: 1.4-9.9) and fatal outcome (OR: 2.2; 95% CI: 1.0-4.7) [33, 61] . Other studies have reported increased risk of developing ALRI in children with RSV-HRV, RSV-hMPV and RSV-PIV-3 co-infections but not with RSV-influenza co-infection [27] , and longer hospitalization length and oxygen requirements in RSV-HRV coinfected toddlers [49] . In a large study of children and adults with radiologically confirmed pneumonia in Thailand, single hBoV infection was not associated with ALRI hospitalization. However, hBoV co-detection with RSV, HRV and PIV was associated with wheezing and signs of respiratory distress more frequently than RSV, HRV and PIV single infections [43] .

The WHO-proposed case definition for pneumonia, part of the integrated management of childhood illnesses (IMCI) strategy that has saved the lives of [67] OR: Odds ratio; y: Years.

Review www.expert-reviews.com millions of children in the developing world [89] , is a highly sensitive albeit poorly specific case definition aimed to maximize the detection of potentially life-threatening ALRI episodes and prompt the rapid initiation of life-saving antibiotic therapy. Respiratory and non-respiratory illnesses might both fulfill this all-embracing definition, but not all patients with this clinical presentation may benefit from antibiotic therapy, particularly if the cause of their ALRI is exclusively a viral infection. Furthermore, in malaria-endemic countries, severe malaria might also present with respiratory distress or tachypnea [48] . For these reasons, given the scarcity of antibiotics (particularly wide-spectrum ones such as third-generation cephalosporins) in many developing settings, together with the emergence of antimicrobial resistance to those commonly available [90] , it is important to identify features that could reliably distinguish viral from bacterial pneumonia, which could clearly have relevant management and public health implications for clinicians and policy makers in developing countries.

In developed countries, the diagnosis of pneumonia relies on a combination of clinical signs and symptoms, radiological results and laboratory tests [91, 92] . In developing countries, hospitals outside urban areas rarely have x-ray facilities or access to laboratory tests such as procalcitonin (PCT) or C-reactive protein (CRP) and diagnostic biomarkers are usually limited to clinical research. Thus, in such contexts, diagnosis is often purely clinical, although standardized x-ray-based case definitions have been proposed by WHO for their use in epidemiological studies or clinical trials [93] . A study in Sweden with 346 pediatric cases with confirmed pneumonia who underwent extensive microbiological tests concluded that x-ray features had no relation to etiology [94] . Authors described hyperinflation and interstitial infiltrates more frequently in viral pneumonia and more alveolar infiltrates in bacterial pneumonia, but those descriptions were not specific. However, they found a relation with age and concluded that age might be a confounder in x-ray interpretation. A study carried out in China describing the x-ray features of 210 pediatric cases less than 15 years of age with viral pneumonia reported that 63% of patients had patchy areas of consolidation, 15% had interstitial infiltrates and 7% had lobar consolidation [95] . Bilateral affectation of lower lobes was frequent. The authors found that ADV-related pneumonia was associated with interstitial infiltrates and seasonal influenza A (H1N1) with diffuse areas of air space consolidation. They found no specific features related to influenza B or PIV pneumonia. However, respiratory viruses commonly causing viral pneumonia were not tested for. Another study in Thailand of 1067 children under the age of 2 years described a significant relationship between RSV-associated pneumonia and interstitial infiltrates [26] . Interestingly, 30% of the pneumonia cases showing lobar consolidations were positive for RSV. In a similar study from Brazil, 54% of RSV-positive patients and 51% of RSV-negative patients had identical interstitial infiltrates and no relation could be established between clinical features and etiology [96] . Most of the studies carried out in a large variety of settings have reported similar results; the most frequent pattern of viral pneumonia (with RSV being the most studied virus) includes interstitial or peribronchial infiltrates, but alveolar or lobar consolidation is not a rare finding (7-30% of viral pneumonias), and mixed patterns are frequent both in viral and bacterial-confirmed pneumonia episodes [21, [97] [98] [99] [100] . Thus, it is fair to conclude that etiologic diagnosis (specific respiratory virus or virus vs bacteria) cannot and should not be made on the basis of x-ray features alone in pediatric pneumonia [101, 102] .

In adults, radiologic findings in viral pneumonia are variable and highly overlapping [103] . Moreover, the corroboration of a lobar consolidations and/or pleural effusion is not rare in adult viral pneumonia [79, 81] . In a series of Kenyan adult patients with viral pneumonia, lobar and multilobar consolidation patterns were seen in 15 patients while patchy consolidation was seen only in one [78] . Although the study was small, it is noteworthy that lung aspirates were performed to rule out bacterial disease. However, 11 patients were HIVinfected and the radiological pattern could have been altered by this condition.

Most clinicians in developing countries rely on their clinical evaluation for an initial orientation of the probable etiology of their patients, despite the poor specificity of clinical symptoms for that purpose. A study carried out at Turku University Hospital (Finland) of 4277 children with laboratory-confirmed viral respiratory infections compared clinical features of eight different respiratory viruses (HRV, RSV, ADV, PIV-1, PIV-2, PIV-3, influenza virus A and influenza virus B), and found that overlapping symptomatology was frequent [13] . Overlapping clinical presentation is also common in developing countries, and more importantly, viral pneumonia signs and symptoms seem to overlap with those of bacterial pneumonia. In a study of 226 children less than 5 years of age with ALRI from Thailand, the authors were unable to identify clinical signs to differentiate viral from bacterial etiology [100] . This was also observed in a study of 214 children under 14 years of age in Sudan [104] . Other studies have compared virus-positive pneumonia versus virus-negative pneumonia and failed to identify significant differences. Low sensitivity of bacterial diagnosis, mostly based on blood cultures, may underestimate viralbacterial co-infections in the virus-positive group leading to conflicting results [44, 105] . However, wheezing has shown significant association with viral pneumonia in some studies, and was present in 17-64% of children and 32% of adults [79, 106] . RSVrelated ALRI usually presents with crackles, wheezing, nasal flaring, lower chest indrawing, rhinorrhea and nasal obstruction more frequently than other viruses [96, [107] [108] [109] . Unfortunately, none of those clinical features are clearly specific of RSV infection and wheezing has also been associated with HRV (particularly to HRV-C), hMPV and hBoV [43, 58, 60, 61, 110] . Reactive airway disease as a sequel of previous viral infections leading to repeated wheezing episodes and readmissions has been described in RSV infections, but also after influenza-related ALRI [20, 105] . In most studies, RSV has been characterized as having more severe presentation in terms of oxygen requirements, hypoxemia and signs of respiratory distress [50, 58, 108] , but other studies found HRV infections to be more severe in both children and adults [49, 79] , and finally some studies concluded severity was not associated with any virus [44, 111, 112] . Case fatality rates have been reported for RSV-associated ALRI (1.9-7.5% in children from different settings), severe influenzaassociated ALRI (4% in <12 years in rural Kenya), influenzaassociated ALRI (0.3-0.4% in children and adults series in Kenya) and hMPV-associated ALRI (5.9% in Indonesia) among the most pathogenic respiratory viruses [35, 59, [106] [107] [108] . In addition, avian influenza A (H5N1) may be associated with a case fatality rate as high as 33% with early antiviral treatment or 80-93% without treatment [113] [114] [115] [116] .

In developed countries, serum biomarkers such as PCT and CRP are used for distinguishing viral from bacterial infections, especially in children. Serum PCT and CRP levels increase in bacterial infections above a cutoff of 1-5 ng/ml and 15-100 mg/l, respectively [117] . Other commonly studied biomarkers, including IL-6, IL-8, IL-18, IFN-a, TNF-g, lipopolysaccharide-binding protein or heparin-binding protein have not shown higher sensitivity, specificity or predictive value than PCT or CRP for that purpose [118] [119] [120] . In a meta-analysis comparing PCT and CRP for differentiating bacterial from viral infections, PCT was more sensitive and specific and had a higher false discovery rate (Q value) than CRP [117] . In developing countries, affordable, rapid and simple diagnostic tools for that purpose are crucial to assure adequate management of antibiotics, especially in view of the low specificity of clinical features. PCT and CRP have proved to be useful markers for bacterial diagnosis in African settings [121] [122] [123] [124] . However, serum levels of PCT and CRP increase in patients with malaria infection and hence may compromise their utility in malariaendemic settings [125] [126] [127] . Further research in this area should be undertaken with the aim of developing a rapid diagnostic test, ideally a point-of-care test that is capable of identifying the underlying etiology of infection in severely ill patients at admission.

Antivirals are rarely used in developing countries, except for avian influenza A (H5N1) cases where oseltaminvir, amantadine, rimantadine and rivabirin have been tested with good results if initiated promptly [116] . Lack of rapid etiologic diagnosis renders this option unsuitable for clinicians from resource-constrained areas. Following WHO recommendations [128] , antibiotics are initiated in patients fulfilling the WHO clinical pneumonia case definition. Passive immunization through the use of specific monoclonal antibodies has been used in developed countries for the management of RSV infections, particularly among highly selected high-risk populations such as extreme preterms and congenital heart defect patients during epidemics. Its prohibitive price, however, makes it an unrealistic option in developing countries. Thus, prevention and control of viral respiratory diseases should primarily be focused on vaccines. Unfortunately, there are no registered vaccines against respiratory viruses suitable for use in children younger than 6 months of age, which is the population at highest risk [31, 129] . For older children and adults, the only available vaccine in the market is that against seasonal influenza, although this vaccine has not been included in the expanded program of immunization for children. Immunization of pregnant women relying on the protectiveness of mother-to-child transferred antibodies, and immunization of post-partum mothers and household contacts have been studied as a strategy to reduce influenza virus burden in young children with promising results [130] [131] [132] . A polyvalent vaccine against RSV and PIV-3 (MEDI-534) is being evaluated in Phase I trials with good safety profile [133] . Vaccines against hMPV and HRV are still in pre-clinical stages and their widespread availability cannot be expected in the short-term [134, 135] .

In developing countries, similar to what occurs in more developed settings, respiratory viruses are an important cause of pneumonia, particularly among young children. However, their real burden is presumably heavily underestimated. The pathogenic role of specific viruses (or viral subtypes) detected in the upper respiratory tract of patients with pneumonia still requires further clarification. Thus, well-designed case-control studies providing robust data and pathogen-specific attributable disease fractions are required, in addition to new diagnostic methods or biomarkers clearly differentiating pathogens which colonize from pathogens which cause disease. Homogenization in clinical and radiological definitions, inclusion criteria and laboratory tests are also necessary to allow comparisons among studies and clearly detect priorities for public health policy makers. Only then, the real and underexposed burden of viral pneumonia in resource-constrained settings will emerge in its true magnitude and significance.

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

• Despite great reductions in child mortality over the last decade, pneumonia remains the major killer of young children globally, accounting for 18% of the under-5 mortality. In recent years, attention has shifted toward non-bacterial causes of pneumonia, and more specifically, to viral-attributable respiratory infections. Data of viral pneumonia from developing countries are scarce.

• In developed countries, the highest incidence of acute respiratory infections (ARIs) is evidenced among children younger than 5 years of age, falling dramatically after 15 years of age and increasing again among adults older than 75 years of age. The few available data from the developing world suggests similar age-distribution tendencies.

• When considering only the most comprehensive studies (detection by PCR of at least 10 viruses in study populations larger than 500 patients over a minimum 12-month period), the prevalence of viral infections in pediatric pneumonia cases ranged from 47 to 69%, with human rhinovirus, respiratory syncytial virus, influenza virus, adenovirus and human metapneumovirus being the most commonly detected pathogens. In adult pneumonia cases, human rhinovirus and influenza are the most frequently detected viruses.

• Causality cannot be inferred from a positive viral isolate in a respiratory sample, especially from upper respiratory tract samples, given lack of controls in most studies.

• Overlapping clinical and radiological presentation is common in viral pneumonia cases caused by different respiratory virus, and more importantly, viral pneumonia signs and symptoms seem to overlap with those of bacterial pneumonia.

• Serum biomarkers used in developed countries to distinguish between viral and bacterial infection such as procalcitonin and C-reactive protein increase in patients with malaria infection compromising their utility in malaria-endemic settings.

• There are no registered vaccines against respiratory viruses suitable for use in children younger than 6 months of age, which is the population at highest risk. 2), S190-S199 (2012).

• Study including a comparison of different diagnosis methods and odds ratios of severe and very severe pneumonia by virus. 

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Community-acquired pneumonia in Chile: the clinical relevance in the detection of viruses and atypical bacteria

Aetiology, outcome, and risk factors for mortality among adults with acute pneumonia in Kenya

Acute lower respiratory infections in >/= 5 yearold hospitalized patients in Cambodia, a low-income tropical country: clinical characteristics and pathogenic etiology

An early report from newly established laboratory-based influenza surveillance in Lao PDR. Influenza Other Respir

The incidence and aetiology of hospitalised community-acquired pneumonia among Vietnamese adults: a prospective surveillance in Central Vietnam

Viral etiologies of lower respiratory tract infections among Egyptian children under five years of age

Respiratory viral coinfections identified by a 10-plex real-time reverse-transcription polymerase chain reaction assay in patients hospitalized with severe acute respiratory illness-South Africa

Respiratory viral infections detected by multiplex PCR among pediatric patients with lower respiratory tract infections seen at an urban hospital in Delhi from

RNA viruses in community-acquired childhood pneumonia in semi-urban Nepal

a cross-sectional study

Spectrum of respiratory viruses circulating in eastern India: prospective surveillance among patients with influenza-like illness during 2010-2011

Viral and atypical bacterial etiology of acute respiratory infections in children under 5 years old living in a rural tropical area of Madagascar

Viral etiologies of acute respiratory infections among hospitalized Vietnamese children in Ho Chi Minh City

Integrated management of childhood illness by outpatient health workers: technical basis and overview. The WHO Working Group on Guidelines for Integrated Management of the Sick Child

Antimicrobial drug resistance trends of bacteremia isolates in a rural hospital in southern Mozambique

New guidelines for the management of adult community-acquired pneumonia

British Thoracic Society guidelines for the management of community acquired pneumonia in children: update

Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies

Radiological findings in children with acute pneumonia: age more important than infectious agent

Radiological findings in 210 paediatric patients with viral pneumonia: a retrospective case study

Prevalence and clinical features of respiratory syncytial virus in children hospitalized for community-acquired pneumonia in northern Brazil

Respiratory syncytial virus-associated lower respiratory diseases in hospitalised pre-school children in Ibadan

Viral etiology of pneumonia in a cohort of newborns till 24 months of age in Rural Mirzapur

Viral etiology in hospitalized children with acute lower respiratory tract infection

Epidemiology of acute respiratory infections in young children from Thailand

Lower respiratory infections in children

Etiology of community acquired pneumonia in children 2-59 months old in two ecologically different communities from Peru

Viral pneumonias in adults: radiologic and pathologic findings

Viral pathogens and clinical manifestations associated with acute lower respiratory tract infections in children of the Sudan

Severe lower respiratory tract infection in early infancy and pneumonia hospitalizations among children

The clinical spectrum of respiratory syncytial virus disease in The Gambia

Epidemiology and clinical presentation of respiratory syncytial virus infection in a rural area of southern Mozambique

Clinical presentation and severity of viral community-acquired pneumonia in young Nepalese children

Incidence and severity of respiratory syncytial virus pneumonia in rural Kenyan children identified through hospital surveillance

Association between human rhinovirus C and severity of acute asthma in children

Respiratory virus infections in hospitalized children and adults in Lao PDR. Influenza Other Respir

Viral pathogens of acute lower respiratory infections in pre-school Nigerian children and clinical implications of multiple microbial identifications

Review of clinical symptoms and spectrum in humans with influenza A/ H5N1 infection

Risk parameters of fulminant acute respiratory distress syndrome and avian influenza (H5N1) infection in Vietnamese children

Avian influenza A (H5N1) in 10 patients in Vietnam

Clinical characteristics of 26 human cases of highly pathogenic avian influenza A (H5N1) virus infection in China

Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis

Evaluation of potential biomarkers for the discrimination of bacterial and viral infections

Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections

Combination of biomarkers for the discrimination between bacterial and viral lower respiratory tract infections

The diagnostic and prognostic accuracy of five markers of serious bacterial infection in Malawian children with signs of severe infection

C-reactive protein and procalcitonin in the evaluation of the efficacy of a pneumococcal conjugate vaccine in Gambian children

Use of procalcitonin and C-reactive protein to evaluate vaccine efficacy against pneumonia

Usefulness of C-reactive protein to define pneumococcal conjugate vaccine efficacy in the prevention of pneumonia

Procalcitonin and C-reactive protein for invasive bacterial pneumonia diagnosis among children in Mozambique, a malaria-endemic area

Procalcitonin and C-reactive protein as predictors of blood culture positivity among hospitalised children with severe pneumonia in Mozambique

Serum biomarkers for the diagnosis of malaria, bacterial and viral infections in children living in malaria-endemic areas

World Health Organization. Pocket Book for Hospital Care of Children: Guidelines for the Management of Common Illness with Limited Resources

Influenza and respiratory syncytial virus (RSV) vaccines for infants: safety, immunogenicity, and efficacy

Impact of Postpartum Influenza Vaccination of Mothers and Household Contacts in Preventing Febrile Episodes, Influenza-like Illness, Healthcare Seeking, and Administration of Antibiotics in Young Infants During the 2012-2013 Influenza Season

Impact of maternal immunization on influenza hospitalizations in infants

Effectiveness of maternal influenza immunization in mothers and infants

Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children

A combination vaccine for allergy and rhinovirus infections based on rhinovirus-derived surface protein VP1 and a nonallergenic peptide of the major timothy grass pollen allergen Phl p 1

Recent developments with live-attenuated recombinant paramyxovirus vaccines

•• Comprehensive review of the global burden of childhood pneumonia. We included all studies regardless of sampling and detection methods. After exclusion of duplicates (140), we further excluded guidelines, studies focused on specific population (e.g., leukemia patients, ventilator-associated pneumonia, travellers, nosocomial pneumonia) and small series of cases. Data was extracted for study location, period of study, study design, sample size, clinical diagnosis, sample type, diagnostic test, aetiological agents investigated, and incidence of viral infections. Studies that did not report data on a complete year (or multiples of a year) were not included in the Epidemiology section.